Osteoarthritis (OA), particularly knee OA, is among the top 15 causes of disability and the main reason for joint replacement at a cost of over $30 billion/year. Knee OA is typically a slowly progressive disorder but for a recently identified subset the disease progresses with dramatic rapidity. These individuals develop more frequent and severe knee pain, and are 16 times more likely to require a total knee replacement.] Since this is a novel observation, we do not yet know whether individuals experiencing [accelerated knee OA (AKOA) is a distinct disease or an accelerated form of knee OA. Determining factors that differentiate or identify AKOA could lead to preventive strategies and uncover therapeutic targets. Our goals are to test if AKOA can be uniquely characterized by: (i) anatomical characteristics associated with injuries and abnormal loading, (ii) biochemical factors that compromise structures (glucose homeostasis, inflammation), (iii) certain types of instigating pathology, and (iiii) distinct pathological processes.] To achieve these goals we propose to perform a nested case-control study with three groups selected from the Osteoarthritis Initiative. The Osteoarthritis Initiative is an outstanding study that conducts annual evaluations; including magnetic resonance images, x- rays, and clinical measurements; of people with or at risk for knee OA. The three groups we propose to examine will be [1) knees that develop AKOA, 2) knees that develop common OA,] and 3) knees with no OA. AKOA will be defined as knees that progress from no radiographic OA at baseline to end-stage OA within 48- months. Common knee OA will be defined as knees with no radiographic OA at baseline but increase in radiographic scoring within 48 months (excluding those defined as AKOA). Finally, no OA will be knees with no radiographic OA and do not progress. We will assess annual MR images in the sample to identify and quantify structural changes in the knee. We will also perform assays to measure [baseline glucose balance and systemic] inflammation. Finally, we will also use serum and urine biomarker data provided by the OAI to measure bone and cartilage turnover. [These findings could lead to preventive strategies and uncover therapeutic targets. Furthermore, the insights generated from this study may generalize to regular knee OA, expanding the overall field.]